Strengthening the Interface of Evidence-Based Decision Making Across European Regulators and Health Technology Assessment Bodies

ObjectivesAccess to medicines in Europe depends on a benefit-risk decision taken by regulators and a relative effectiveness assessment performed by health technology assessment bodies (HTABs) to inform, as one element, a reimbursement decision. Although various similarities in evidence needs exist, understanding of their needs is currently suboptimal and therefore the evidence generated does not always meet their needs. Subsequently, delays in decision making can be expected, negatively affecting access. To overcome this, this study reviewed the evidentiary needs of European regulators and HTABs at European level and analyzed how their collaboration can further facilitate optimal evidence generation plans, evidence use, and evidence presentation.MethodsThrough systematic literature review, expert interviews, and pairwise comparison of assessment reports by the European Medicines Agency and European network for health technology assessment, respective clinical evidence requirements and impact of product-specific collaboration between European Medicines Agency and HTABs were established.ResultsClinical evidence needs are quite similar but differences exist in comparator choice, preferred efficacy endpoints, and target population. Results of the impact of collaboration to date were mixed: preapproval joint advice procedures were successful and highly valued by all stakeholders; information exchange at the time of regulatory decision is coming together, yet the European Public Assessment Report can be further optimized; and collaboration on postlicensing evidence generation requirements shows potential but needs solidifying.ConclusionsThese findings demonstrate the potential to further improve the evidence utilization across stakeholders to avoid duplication and streamline decision making, to ultimately improve access to medicines for European patients.     

Use of Real-World Evidence for Regulatory Approval and Coverage of Medical Devices: A Landscape Assessment

ObjectivesTo enhance the generalizability of the evidence it reviews, the US Food and Drug Administration (FDA) has encouraged manufacturers to expand the submission of real-world evidence (RWE). The extent to which this evidence, which is generated outside of research settings, can support decision making remains unclear. We described the current use of RWE for medical devices, assessed manufacturers’ challenges in generating and using it for regulatory and coverage decisions, and identified opportunities to expand its use.MethodsWe conducted 27 solo and group interviews with FDA officials and representatives of device manufacturers, payers, and health technology assessment organizations. All interviews used a semistructured protocol and were transcribed to allow thematic analysis.ResultsAccessing and linking real-world data sources, identifying unique devices, capturing longitudinal data, limited staff expertise, and uncertain return on investment have hampered efforts to use real-world data. Many companies in our sample were conducting research using real-world data, but none had submitted RWE as the primary evidence supporting a premarket approval. FDA guidance was helpful, but regulatory requirements remained ambiguous and examples of successful regulatory decisions based on RWE were limited. Payers mainly used RWE to supplement experimental evidence in coverage decisions, evaluated both types of evidence in similar ways, and had concerns about the rigor of RWE.ConclusionsTechnical challenges may slow efforts to generate and use RWE in the near term. Additional regulatory guidance and examples, greater use of rigorous study designs and analytic methods, and continued stakeholder engagement could accelerate the use of RWE.     

Improving Transparency to Build Trust in Real-World Secondary Data Studies for Hypothesis Testing—Why,What, and How: Recommendations and a Road Map from the Real-World Evidence Transparency Initiative

Real-world data (RWD) and the derivations of these data into real-world evidence (RWE) are rapidly expanding from informing healthcare decisions at the patient and health system level to influencing major health policy decisions, including regulatory approvals and coverage. Recent examples include the approval of palbociclib in combination with endocrine therapy for male breast cancer and the inclusion of RWE in the label of paliperidone palmitate for schizophrenia. This interest has created an urgency to develop processes that promote trust in the evidence-generation process. Key stakeholders and decision-makers include patients and their healthcare providers; learning health systems; health technology assessment bodies and payers; pharmacoepidemiologists and other clinical reseachers, and policy makers interested in bioethical and regulatory issues. A key to optimal uptake of RWE is transparency of the research process to enable decision-makers to evaluate the quality of the methods used and the applicability of the evidence that results from the RWE studies.Registration of RWE studies—particularly for hypothesis evaluating treatment effectiveness (HETE) studies—has been proposed to improve transparency, trust, and research replicability. Although registration would not guarantee better RWE studies would be conducted, it would encourage the prospective disclosure of study plans, timing, and rationale for modifications. A joint task force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) recommended that investigators preregister their RWE studies and post their study protocols in a publicly available forum before starting studies to reduce publication bias and improve the transparency of research methods.Recognizing that published recommendations alone are insufficient, especially without accessible registration options and with no incentives, a group of experts gathered on February 25 and 26, 2019, in National Harbor, Maryland, to explore the structural and practical challenges to the successful implementation of the recommendations of the ISPOR/ISPE task force for preregistration. This positioning article describes a plan for making registration of HETE RWE studies routine. The plan includes specifying the rationale for registering HETE RWE studies, the studies that should be registered, where and when these studies should be registered, how and when analytic deviations from protocols should be reported, how and when to publish results, and incentives to encourage registration. Table 1 summarizes the rationale, goals, and potential solutions that increase transparency, in addition to unique concerns about secondary data studies.Definitions of terms used throughout this report are provided in Table 2.     

The development of pharmacological treatment of obesity in children

Childhood obesity is recognized by the World Health Organization as one of the most serious public health challenges of the 21st?century. Current treatment recommendations consider the role of pharmacotherapy in the treatment of childhood obesity, as an adjunct to lifestyle modifications. This article focuses on key requirements for paediatric development of medicines for obesity in Europe with reference to the European Medicines Agency guideline and a review of Paediatric Investigation Plans (PIP) submitted for this condition, under Regulation (EC) No. 1901/2006 on medicines for paediatric use. To date the European Medicines Agency (EMA) received four paediatric investigation plans for childhood obesity. Issues encountered during the assessment of paediatric investigation plans were all related to the characteristics of the patient population, trial design, choice of endpoints, and safety aspects. Although the number of paediatric investigation plans submitted to the European Medicines Agency thus far is limited, current experience highlights the need for clinical trial protocols that are in line with the specific European guideline. Divergent approaches should be discussed with regulatory authorities before paediatric trials are initiated and included in paediatric investigation plans.     

Replication of Randomized,Controlled Trials Using Real-World Data: What Could Go Wrong?

With the growing interest in using real-world evidence (RWE) for regulatory purposes, researchers and policy makers are considering how best to assess the credibility of RWE. Because the randomized controlled trial (RCT) has long been regarded as the gold standard for high-quality research, one approach being pursued is to see to what extent findings from RCTs can be replicated based on analyses of nonrandomized real-world data (RWD). If findings are congruent, the reasoning goes, this would bolster confidence in the underlying RWD sources and validity of the RWE generated. But it is well known that medical interventions perform differently in experimental clinical trials versus real-world clinical practice, reflecting a phenomenon known as the “efficacy-effectiveness gap.” So even with the highest-quality RWD sources and strongest analytic methods, we can and should expect to observe discrepancies in findings between RCTs and RWE. This calls into question the objectives of RCT replication efforts and makes clear that impugning RWD sources and analytic methods for failing to align with RCT findings is inappropriate and, worse, potentially harmful to the growing acceptance of RWE in stakeholder decision making.     

Use of Real-World Evidence in US Payer Coverage Decision-Making for Next-Generation Sequencing–Based Tests: Challenges,Opportunities, and Potential Solutions

ObjectivesGiven the potential of real-world evidence (RWE) to inform understanding of the risk–benefit profile of next-generation sequencing (NGS)–based testing, we undertook a study to describe the current landscape of whether and how payers use RWE as part of their coverage decision making and potential solutions for overcoming barriers.MethodsWe performed a scoping literature review of existing RWE evidentiary frameworks for evaluating new technologies and identified barriers to clinical integration and evidence gaps for NGS. We synthesized findings as potential solutions for improving the relevance and utility of RWE for payer decision-making.ResultsPayers require evidence of clinical utility to inform coverage decisions, yet we found a relatively small number of published RWE studies, and these are predominately focused on oncology, pharmacogenomics, and perinatal/pediatric testing. We identified 3 categories of innovation that may help address the current undersupply of RWE studies for NGS: (1) increasing use of RWE to inform outcomes-based contracting for new technologies, (2) precision medicine initiatives that integrate clinical and genomic data and enable data sharing, and (3) Food and Drug Administration reforms to encourage the use of RWE. Potential solutions include development of data and evidence review standards, payer engagement in RWE study design, use of incentives and partnerships to lower the barriers to RWE generation, education of payers and providers concerning the use of RWE and NGS, and frameworks for conducting outcomes-based contracting for NGS.ConclusionsWe provide numerous suggestions to overcome the data, methodologic, infrastructure, and policy challenges constraining greater integration of RWE in assessments of NGS.     

Endpoints for safety in health technology assessments–The experiences of the Danish Medicines Council

ObjectivesThere are no international guidelines on how the requirements for added clinical value (endpoints) should be prepared in terms of drug safety by entities performing health technology assessments (HTAs). The study aimed to review the Danish Medicines Council's drug safety endpointsMethodsSafety endpoints prepared by the Danish Medicines Council's expert committees were reviewed from their assessment reports for 50 treatments, of which 25 were for the treatment of cancer and 25 were for the treatment of other types of diseases. Similarities and differences were identifiedResultsThe 139 endpoints for safety were grouped into 14 categories. The use of endpoints varied and all endpoints were based on an expert assessment. Serious adverse reactions/events were used as an endpoint in most of the cases: 43.2% (N=60)/15.8% (N=22), following treatment discontinuation based on four different causes 16.4% (N=32). A numerical grading scale for adverse events were predominately used for endpoints for cancer treatment (19.8%, N=20 vs. 2.1%, N=2)ConclusionsThe variation in the use of endpoints reflects the complexity of safety assessments and the need for more standardization to promote stringency and transparency. The authors propose five recommendations for actions, which may promote more generalizability and transparency. International HTA entities and researchers are also encouraged to investigate the possibilities of establishing a universal grading system for adverse events and to develop international guidelines for safety assessment in HTAs.Public interest abstractNew medicines often have to be evaluated against the treatment already available in order to compare effectiveness, safety and price. If one treatment is superior, it will often be referred to as having added clinical value. This evaluation is known as a health technology assessment (HTA). All medicines can cause side effects and the assessment of safety in HTAS is therefore essential. No international guidelines for drug safety assessment in HTAs however exist. The requirements for safety prepared by the Danish Medicines Council's expert committees were therefore reviewed from their assessment reports for 50 treatments in order to present their approach to drug safety assessment. A total of 139 safety requirements, also referred to as endpoints, were identified. The use of endpoints varied which reflects the complexity of safety assessments and the need for more standardization to promote stringency. The authors propose five recommendations for actions, which may promote more generalizability and transparency in Denmark and internationally.     

Prohibiting or ‘managing’ conflict of interest? A review of policies and procedures in three European drug regulation agencies

In light of debates about the relationship between interests and scientific expert judgments, and the potential for declarations of conflict of interest (COI) to minimize corporate bias, we reviewed the approach to COI in 3 European drug regulatory bodies. These bodies were the Irish Medicines Board, the Medicines and Healthcare products Regulatory Agency in the United Kingdom and the European Medicines Agency in the European Union. Official statements about COI laws and codes of practice in the 3 contexts suggest that COIs are prohibited. In practice, the approaches to COI in the 3 drug regulatory agencies presuppose and promote the ideas that COIs cannot and need not be eliminated as the risk of bias can be managed. Because the evidence about if and how COI affects micro-level decision-making in drug regulatory authorities is neither complete nor comprehensive, we advocate a precautionary principle model. Under this model COI would be prohibited on the grounds that it might influence the outcome of regulatory decisions.     

Contributions of cost-effectiveness analyses (CEA) to influenza vaccination policy for older adults in Europe

This review describes the importance of economic evaluations and real-world evidence (RWE) for the assessment of enhanced influenza vaccines for older adults in Europe. Individuals ≥65 years of age are at increased risk of severe influenza outcomes and many countries in Europe recommend enhanced vaccines for this population to mitigate immunosenescence. Some National Immunization Technical Advisory Groups (NITAGs) may preferentially recommend a specific enhanced vaccine, necessitating comparative economic evaluation and estimation of relative vaccine effectiveness between enhanced vaccine options in the absence of direct head-to-head efficacy data. Distinct approaches to economic modeling and cost-effectiveness analysis (CEA) guide national vaccination policies in Europe, including how underlying data, such as RWE, are used in these models. RWE is an important evidence source for input into CEA models based on disease factors (e.g., antigenic shift and seasonal variation) and practical factors (e.g., limitations of performing multiple randomized clinical trials to capture seasonal variation; the need to obtain relevant patient-oriented, real-world endpoints, such as hospitalizations). CEA is considered crucial to vaccine assessment among certain countries in Europe, but further harmonization of economic evaluations, including the use of RWE, across NITAGs in Europe may be of benefit, alongside standardized approaches for vaccine appraisal. In the future, more countries may use RWE as an input in CEA models to support NITAG recommendations for enhanced influenza vaccines in older populations, especially considering the value of RWE for the assessment of influenza epidemiology and vaccine effectiveness as stated by the World Health Organization, and the availability of a broad RWE base for certain enhanced vaccines.     

Improving the Contribution of Regulatory Assessment Reports to Health Technology Assessments—A Collaboration between the European Medicines Agency and the European network for Health Technology Assessment

In response to a recommendation from the Pharmaceutical Forum, the European Medicines Agency and the European network for Health Technology Assessment initiated a collaboration with the aim to improve the contribution regulatory assessment reports can make to the assessment of relative effectiveness of medicinal products by health technology assessment bodies. This collaboration on improving European Public Assessment Reports (EPARs) started in February 2010 and was performed over 2 years. As a result, the templates for preparing EPARs were revised to better address the needs of heath technology organizations. The better understanding of information needs was a key outcome of the collaboration. To ascertain whether these template changes led to the inclusion of relevant information, a review of a small set of EPARs for recently approved medicinal products was carried out in parallel by both the European network for Health Technology Assessment and the European Medicines Agency. This report provides an account of this project on improving EPARs, which is part of the ongoing dialogue between regulators and health technology assessment bodies on a European level to support policymaker decisions in the future.     

Effect of Crossover in Oncology Clinical Trials on Evidence Levels in Early Benefit Assessment in Germany

Background

In oncology clinical trials, crossover is used frequently but may lead to uncertainties regarding treatment effects.

Despite criticism of the FDA review process, new cancer drugs reach patients sooner in the United States than in Europe

The US Food and Drug Administration is often criticized as inefficient compared to its European counterpart, the European Medicines Agency. This criticism is especially common in the field of oncology, where severely ill patients have few therapeutic options. We conducted a direct drug-to-drug comparison of the two regulatory agencies' approvals of new oncology drugs. We found that contrary to public assertions, the median time for approval for new cancer medicines in the United States was just six months--and that these new anticancer medicines are typically available in the United States before they are in Europe. Our findings reinforce the need for strong financial and public support of the Food and Drug Administration, so that such medicines can continue to be made available speedily to patients in need.     

Consumer's risk in the EMA and FDA regulatory approaches for bioequivalence in highly variable drugs

The 2010 US Food and Drug Administration and European Medicines Agency regulatory approaches to establish bioequivalence in highly variable drugs are both based on linearly scaling the bioequivalence limits, both take a ‘scaled average bioequivalence’ approach. The present paper corroborates previous work suggesting that none of them adequately controls type I error or consumer's risk, so they result in invalid test procedures in the neighbourhood of a within‐subject coefficient of variation osf 30% for the reference (R) formulation. The problem is particularly serious in the US Food and Drug Administration regulation, but it is also appreciable in the European Medicines Agency one. For the partially replicated TRR/RTR/RRT and the replicated TRTR/RTRT crossover designs, we quantify these type I error problems by means of a simulation study, discuss their possible causes and propose straightforward improvements on both regulatory procedures that improve their type I error control while maintaining an adequate power. Copyright © 2015 John Wiley & Sons, Ltd.     

Europäische Gesetzgebung zu besonderen Therapierichtungen

Medicinal products from complementary and alternative medicine are in Germany a regular part of the health care system. Herbal, homeopathic, anthroposophic and traditional medicinal products are highly accepted by the population. The German Medicines Act obliged the competent authorities to consider the particular characteristics of complementary and alternative medicines. The European regulatory framework defined the status of herbal medicinal products, traditional herbal medicinal products and homeopathic medicinal products within the directive 2001/83/EC. The committee for herbal medicinal products (HMPC) was established at the European Medicines Agency in London (EMEA); for homeopathic medicinal products there is a specific working group established by the Heads of Medicines Agencies. Harmonisation of medicinal products from complementary and alternative and traditional medicine in Europe was enforced by implementation of directive 2001/83/EC in national legislations of member states. The provisions of this directive will substantially influence the development of the European market during the forthcoming years.     

Real-World Evidence: Useful in the Real World of US Payer Decision Making? How? When? And What Studies?

Objectives

To examine how real-world evidence (RWE) is currently perceived and used in managed care environments, especially to inform pharmacy and therapeutic (P&T) committee decisions, to assess which study factors (e.g., data, design, and funding source) contribute to RWE utility in decisions, and to identify barriers to consideration of RWE studies in P&T decision making.

Erfahrungsbericht aus dem Ausschuss f��r neuartige Therapien (CAT)

Advanced therapy medicinal products (ATMP) are highly innovative and complex medicines. They comprise gene therapy medicinal products, somatic cell therapy medicinal products, and tissue-engineered products (TEP). With the European Regulation on ATMP that came into force in 2008, a consolidated regulatory framework was created, where the Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMA) plays a central role. This article discusses pitfalls and challenges that the CAT has experienced in its discussions of various procedures. Often ATMPs are developed by small and medium-sized enterprises (SME) which also face nonscientific challenges. The CAT wishes to meet these challenges on a scientific and regulatory level during its 2010-2015 work program.     

A Comparison of 7 Oncology External Control Arm Case Studies: Critiques From Regulatory and Health Technology Assessment Agencies

ObjectivesThe development of accelerated approval programs for high morbidity and unmet need conditions has driven the use of single-arm studies in drug development. Regulatory and health technology assessment (HTA) agencies are recognizing that high-quality external control arms (ECAs), built using real-world data, can reduce uncertainties arising from single-arm studies. This review compared 7 case studies of regulatory and HTA agencies’ evaluations of oncology ECAs.MethodsFood and Drug Administration multidisciplinary reviews for oncology submissions from 2014 to 2021 were screened to identify 7 cases (2 blinatumomab indications, avelumab, and erdafitinib, entrectinib, trastuzumab deruxtecan, and idecabtagene vicleucel) with ECAs to support efficacy claims. Regulatory (Food and Drug Administration, European Medicines Agency, Health Canada) and HTA (pan-Canadian Oncology Drug Review, National Institute for Health and Care Excellence, Federal Joint Committee, Haute Autorité de Santé, and Pharmaceutical Benefits Advisory Committee) submissions for these cases were reviewed. The decision makers’ ECA critiques and the level of influence on the decision were analyzed and categorized.ResultsAcross case studies, selection bias and confounding were the most common ECA critiques. Nevertheless, agreement in critiques between and among regulators and HTA bodies was low. ECA influence on agencies’ decisions also varied.ConclusionsEvaluating the same ECA evidence, agencies focused on methodologic issues (ie, selection bias and confounding), but were often not aligned on their critiques. Further research is needed to fully characterize how agencies evaluate ECAs. This study is a first step in critically evaluating agencies’ critiques of ECAs and highlights the need for future guidance development around ECA design and generation.     

Presence of Nitrosamine Impurities in Medicinal Products

In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: N -nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequently replaced with therapeutic alternatives.Key Words: carcinogenicity, metformin, NDEA, NDMA, ranitidine, sartans     

Use of Real-World Evidence to Support FDA Approval of Oncology Drugs

ObjectivesReal-world evidence (RWE) has gained increased attention in recent years as a complement to traditional clinical trials. The use of RWE to establish the efficacy of oncology drugs for Food and Drug Administration (FDA) approval has not been described. In this paper, we review 5 recent examples where RWE was submitted in support of the FDA approvals of original or supplementary indications for oncology drugs.MethodsTo identify cases where RWE was used, we reviewed drug approval packages available at Drugs@FDA for oncology drugs approved between 2017 and 2019. Five cases were selected to present a broad overview of different types of RWE, different circumstances under which RWE has been used for regulatory approvals, and how FDA evaluated the data in each case. The type of RWE submitted, the indication, limitations identified by FDA reviewers, and the outcome of the submission are discussed.ResultsRWE, particularly historical controls for rare or orphan indications, has been used to support both original and supplementary oncology drug approvals. Types of RWE included data from electronic health records, claims, post-marketing safety reports, retrospective medical record reviews, and expanded access studies. Small sample sizes, data quality, and methodological issues were among concerns cited by FDA reviewers.ConclusionBy bridging the gap between the constraints of the trial setting and the realities of clinical practice, RWE can add value to a regulatory submission. These early examples provide insight into how regulators evaluated RWE submitted as evidence of efficacy for oncology drugs.